NPHP3 – Senior-Loken Syndrome

Senior-Loken syndrome (SLS) is an autosomal recessive ciliopathy characterized by nephronophthisis and early-onset retinopathy (MONDO:0017842). Despite inclusion of NPHP3 in gene panels and its known role in nephronophthisis, a retrospective series of 74 SLS patients across 70 families identified biallelic variants in CEP290, IQCB1, NPHP1, NPHP4, and WDR19 but none in NPHP3 (PMID:36990420). This absence of human SLS cases limits the genetic evidence for NPHP3.

Functional studies in a mouse hypomorphic pcy model demonstrate that Nphp3 loss leads to cystic kidney disease and tapetoretinal degeneration resembling SLS, whereas complete knockout results in embryonic lethality, situs inversus, and cardiac defects (PMID:18371931). Mechanistically, nephrocystin-3 interacts with inversin to regulate canonical and noncanonical Wnt signaling, and deficient Nphp3 disrupts planar cell polarity in Xenopus, mirroring the clinical spectrum of nephronophthisis with retinal involvement.

Key Take-home: While human biallelic NPHP3 variants have not yet been documented in Senior-Loken syndrome cohorts, concordant functional data support its candidacy and warrant inclusion in diagnostic testing panels.

References

• NPJ genomic medicine • 2020 • Retrospective case series of Senior-Loken syndrome variants PMID:36990420
• American journal of human genetics • 2008 • Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia PMID:18371931

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